Cyclin localization controls activity

Exiling a protein from the scene of the reaction is one way to manage its activity. Cells adopt this method to reign in the cyclins, proteins that orchestrate the cell cycle. By tracking two cyclins from one mitosis to the next, Tony Hunter of the Salk Institute for Biological Studies in San Diego, California, and his post-doc Jonathon Pines were the first to demonstrate the importance of subcellular location for the molecules.

Cyclins team up with proteins called cyclin-dependent kinases (Cdks) to organize different steps of cell division. Cyclins A and E prompt DNA replication, whereas cyclin B1 pushes the cell to advance from the G₂ phase to mitosis. In the early 1990s, Hunter recalls, researchers were debating whether the various cyclins were interchangeable. Some studies supported the idea, indicating that certain cyclin-Cdk pairs were active at about the same time in the cell cycle and targeted the same molecules. But how interchangeable cyclins could exert disparate effects on the cell was a mystery.

Pines and Hunter proposed a solution, hypothesizing that cyclins triggered different responses because they lingered in different parts of the cell. They tested the notion by using immunofluorescence to follow the A and B1 cyclins through the cell cycle. Cyclin A started moving from the cytoplasm into the nucleus at the beginning of S phase and remained there until being destroyed during prometaphase (Pines and Hunter, 1991). Cyclin B, meanwhile, loitered in the cytoplasm until the beginning of mitosis, when it flooded into the nucleus. It didn't get eliminated until the end of metaphase. The asynchronous movements of the two cyclins suggested that position dictates their function and helped foster “the general realization that the cell cycle is controlled by the spatial separation of regulators from their targets,” says Hunter.

A report published more recently (Moore et al., 2003) confirmed that location determines cyclin function. The researchers modified the sequence of cyclin B1 so that it built up in the nucleus. The altered form provoked DNA synthesis, indicating that cyclin B1 doesn't normally activate this process only because it's excluded from the nucleus until later on.

Other studies have filled in many details of cyclin B1's travels. Instead of biding its time in the cytoplasm early in the cell cycle, cyclin B1 is continually barging into the nucleus, but it keeps getting booted out. A nuclear export sequence in cyclin B1 provokes its ejection through the nuclear membrane (Hagting et al., 1998). Phosphorylation is the cyclin's ticket into the nucleus (Yang et al., 1998; Hagting et al., 1999), and is performed by a protein called polo-like kinase 1 (Toyoshima-Morimoto et al., 2001) and the activated cyclin B1-Cdk complex itself (Jackman et al., 2003).